Abstract 5106: In vitro and in vivo evaluation of WAC-224, a novel quinolone class of topoisomerase II inhibitor for cancer therapy

Abstract

Abstract Introduction: DNA topoisomerases (Topo) are classical but still attractive targets for drug therapy in multiple types of cancers. Topo inhibitors, such as Etoposide and Daunorubicin, have been effectively used; however, their clinical use is often limited by drug resistance in cancer cell population. Therefore, the development of a novel chemical class of Topo inhibitors has been desired to overcome drug resistance. Recently, Vosaroxin (QINPREZO) is identified as a first-in-class anti-cancer quinolone derivative targeting Topo II, which is under development for relapsed or refractory acute myeloid leukemia (AML). In this study, we evaluated the in vitro and in vivo activities of WAC-224, a novel quinolone derivative for Topo II inhibition, for various cancer cell lines including multi-drug resistant cells and in mouse xenograft models, respectively. Materials and Methods: In vitro anti-proliferative activities against over 20 cell lines were determined using WST cell proliferation reagent. Apoptosis was measured by Annexin-V staining. In vivo anti-tumor activity was determined in immunodeficient mice bearing multi-drug resistant human uterine sarcoma MES-SA/DX5. Results: WAC-224 accomplished extensive anti-proliferative activities for cancer cell lines including multi-drug resistant ones with the EC50 range of 0.001 to 1 microM. Especially, in MV4-11 AML cell line, WAC-224 showed a potent and superior anti-proliferative activity compared with Doxorubicin (EC50: 1.4 nM for WAC-224 v.s. 2.5 nM for Doxorubicin). Molecular and cellular mechanisms of WAC-224 were defined as inhibition of human Topo II, induction of G2/M phase cell cycle arrest and apoptosis. Additionally, significant antitumor effects of WAC-224 were confirmed in mouse xenograft models. Furthermore, WAC-224 showed no toxic effect on small intestinal crypts in mice. Conclusion: This study demonstrated that WAC-224 has strong in vitro activities against broad cancer cell types along with the potent in vivo efficacy and well tolerability, without gastrointestinal toxicity. These results indicate that WAC-224 is promised to provide a new therapeutic option for various cancers including multi-drug resistant and hematological ones. Citation Format: Taichi Ueshima, Tomonori Yamaguchi, Kenji Itoh, Naoki Kashimoto, Tatsuya Hirano, Rumiko Shimabara, Yohei Kawakubo, Masayuki Sato, Junpei Yamashita, Akira Yazaki, Koichi Tamura. In vitro and in vivo evaluation of WAC-224, a novel quinolone class of topoisomerase II inhibitor for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5106. doi:10.1158/1538-7445.AM2017-5106